1. health and fitness
2. disease

Chapter 1
General introduction
Wouter Jacobs* and Anton Vonk Noordegraaf*
Department of Pulmonology, VU University Medical Center,
Amsterdam
*
Chapter 1
In 1865 The German physician Klob reported autopsy findings of a patient who had
developed progressive ankle oedema , dyspnoea and cyanosis prior to his death at 59.
In stead of the cardiac pathology he expected, Klob found an impressive narrowing
of the finer branches of the pulmonary artery with localised arteriosclerosis.1 In 1891
Romberg described a similar clinical course in a 24-year old patient.2 Other than
the abnormalities in the pulmonary vessels he also noted a massive right ventricular
hypertrophy.
This disease now known as Pulmonary Arterial Hypertension (PAH) is a rare disease
with an estimated incidence of 1-2/million inhabitants per year for the idiopathic
form.3-5 Reported prevalence of PAH in patients with connective tissue disease varies
from 2-50%6-16 and it can be detected in 0,5% of HIV patients.17-18 By consensus
pulmonary hypertension is defined by a mean pulmonary artery pressure greater than
25mmHg. Pulmonary hypertension may arise due to various underlying alternative
conditions and the clinician must have an understanding of the context in which
PH occurs as different treatment strategies may be necessary in different situations.
The clinical substrates of PH have been catalogued based on their pathological
characteristics, clinical presentations, hemodynamic profiles and therapeutic
outcomes into 5 different groups. The current classification of PH was provided by
consensus at a world symposium of PH specialists held in Venice 2003 and is shown
in table 1.19 PAH is defined as pulmonary hypertension classified in group 1 according
to the Venice classification and is either idiopathic or from the associated etiologies
mentioned.
When examining PAH histopathology characteristics of PH with atheromatous
changes, dilation of large pulmonary arteries and medial hypertrophy and remodelling
of muscular arteries are found. If pulmonary hypertension persists right ventricular
hypertrophy, dilation and ultimately failure are common sequelae. Besides these
histopathologic features common to all causes of Pulmonary Hypertension, each
of the forms of Pulmonary Arterial Hypertension are associated with characteristic
lesions involving both the pre-acinar and intra-acinar arteries. These include
constrictive lesions at the vessel intima, remodelling of the media or adventitia, as
well as complex (plexiform) lesions involving changes of the entire vessel wall. In
addition to constrictive and complex lesions, thrombosis of small vessels is noted
frequently in the absence of evidence to suggest an embolic source. 20
A diagnosis of PAH portends a dismal prognosis and before the advent of PAH
specific therapies median survival of IPAH patients was estimated at 2.8 years.21 The
discovery of prostacyclin I2, in 1976 by Moncada and Vane22 was the first step in the
development of PAH specific therapies and currently there are three different classes
of PAH specific drug therapies which are well established. They are the prostanoids,
the endothelin receptor antagonists and the phosphodiesterase type 5 inhibitors and
target three different pathways involved in abnormal contraction and proliferation of
smooth muscle cells.23 The development of these PAH specific therapies has improved
survival.24,25 However long-term survival in the modern management era remains
poor26 and knowledge on combining these drug therapies is limited. Currently the
prostacyclin I2 analogue epoprostenol is widely perceived as the most potent PAH
10
General introduction
The Venice classification of pulmonary hypertension19
Chapter 1
Table 1
1. Pulmonary Arterial Hypertension (PAH)
1.1 Idiopathic (IPAH)
1.2 Familial (FPAH)
1.3 Associated with (APAH):
1.3.1 Collagen vascular disease
1.3.2 Congenital systemic-to-pulmonary shunts
1.3.3 Portal hypertension
1.3.4 HIV infection
1.3.5 Drugs and toxins related
1.3.6 Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic teleangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy)
1.4 Associated with significant venous or capillary involvement
1.4.1 Pulmonary veno-occlusive disease (PVOD)
1.4.2 Pulmonary capillary hemangiomatosis (PCH)
1.5 Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease
2.1 Left sided atrial or ventricular heart disease
2.2 Left sided valvular heart disease
3. Pulmonary hypertension associated with lung diseases and/or hypoxaemia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Sleep-disordered breathing
3.4 Alveolar hypoventilation disorders
3.5 Chronic exposure to high altitude
3.6 Developmental abnormalities
4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH)
4.1 Thromboembolic obstruction of proximal pulmonary arteries
4.2 Thromboembolic obstruction of distal pulmonary arteries
4.3 Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)
5. Miscelaneous
Sarcoidosis, Histiocytosis X, Lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
specific drug therapy available27 and data corroborating this are reviewed in Chapter 2.
However prostanoid adminstration, either intravenous, subcutaneous or by inhalation,
can be bothersome, and the possibility of oral therapy with either an endothelin
receptor antagonist or a phosphodiesterase-type 5 inhibitor is an attractive alternative.
Aim of this thesis is to describe long-term treatment results in idiopathic PAH patients
treated at the VU University Medical Centre, a referral centre for PAH patients in the
Netherlands. Different treatment strategies were used in different time periods. Untill
2002 the only PAH specific therapy available in the Netherlands was i.v. epoprostenol.
In Chapter 3 we describe treatment results with our current treatment strategy which
11
Chapter 1
involves first-line oral therapy with the endothelin receptor antagonist bosentan and
subsequently addition of alternative PAH specific therapies as needed. Treatment
results in these patients are compared with our historical cohort of patients treated
with first-line i.v. epoprostenol. Subsequently in Chapter 4 we describe efficacy of
prostanoids added to oral therapy after treatment failure on first line therapy. In
Chapter 5 we sought to determine causes of differential treatment effects between
sexes using invasive haemodynamic and cardiac MRI follow-up measurements. In
recent years PAH awareness has improved amongst physicians in the community and
this has lead to increasing patient referrals. In Chapter 6 we consider a predictive model
capable of identifying left diastolic heart failure as a differential cause of pulmonary
hypertension in these patients; obviating the need for right heart catheterisation. To
conclude we summarize current understanding of PAH specific drug treatments and
discuss future prospects in chapter 7.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
12
Klob J. Endarteriitis pulmonalis deformans. Wien Wochenbl 1865;31:45.
Romberg E. Über sklerose der lungen arterie. Dtsch Arch Klin Med 1891;48:197-206.
Abenhaim L, Moride Y, Brenot F, et al. Appetite suppressant drugs and the risk of primary pulmonary
hypertension. International primary pulmonary hypertension study group. N Engl J Med 1996;335:609616.
Group IPPHS: The international primary pulmonary hypertension study. Chest 1994;105:37S-41S.
Appelbaum L, Yigla M, Bendayan D, et al. Primary pulmonary hypertension in Israel: A national
survey. Chest 2001;119:1801-1806.
MacGregor AJ, Canavan R, Knight C, Denton CP, Davar J, Coghlan J, et al. Pulmonary hypertension in
systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford)
2001;40:453-9.
Morelli S, Barbieri C, Sgreccia A, Ferrante L, Pittoni V, Conti F, et al. Relationship between cutaneous
and pulmonary involvement in systemic sclerosis. J Rheumatol 1997;24:81-5.
Murata I, Takenaka K, Yoshinoya S, Kikuchi K, Kiuchi T, Tanigawa T, et al. Clinical evaluation of
pulmonary hypertension in systemic sclerosis and related disorders. A Doppler echocardiographic
study of 135 Japanese patients. Chest 1997;111:36-43.
Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis
of 17 patients. Br J Rheumatol 1996;35:989-93.
Ungerer RG, Tashkin DP, Furst D, Clements PJ, Gong H, Jr., Bein M, et al. Prevalence and clinical
correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983;75:6574.
Yamane K, Ihn H, Asano Y, Yazawa N, Kubo M, Kikuchi K, et al. Clinical and laboratory features of
scleroderma patients with pulmonary hypertension. Rheumatology (Oxford) 2000;39:1269-71.
Morgan C, Knight C, Lunt M, Black CM, Silman AJ. Predictors of end stage lung disease in a cohort of
patients with scleroderma. Ann Rheum Dis 2003;62:146-50.
Pan TL, Thumboo J, Boey ML. Primary and secondary pulmonary hypertension in systemic lupus
erythematosus. Lupus 2000;9:338-42.
Asherson RA, Higenbottam TW, Dinh Xuan AT, Khamashta MA, Hughes GR. Pulmonary hypertension
in a lupus clinic: experience with twenty-four patients. J Rheumatol 1990;17:1292-8.
Alpert MA, Goldberg SH, Singsen BH, Durham JB, Sharp GC, Ahmad M, et al. Cardiovascular
manifestations of mixed connective tissue disease in adults. Circulation 1983;68:1182.
16. Hosoda Y, Suzuki Y, Takano M, Tojo T, Homma M. Mixed connective tissue disease with pulmonary
hypertension: a clinical and pathological study. J Rheumatol 1987;14:826-30.
17. Nunes H, Humbert M, Sitbon O, Morse JH, Deng Z, Knowles JA, et al. Prognostic Factors for survival
in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care
Med 2003;167:1433.
18. Humbert M, Nunes H, Sitbon O, Parent F, Herve P, Simonneau G. Risk factors for pulmonary arterial
hypertension. Clin.Chest Med 2001;22:459-75.
19. Simmoneau G, Galiè N, Rubin L. et al. Clinical classification of pulmonary hypertension. J Am Coll
Cardiol 2004;43, supplement 1(12):S5-S12.
20. Tiachman DB, Snow JL, Pietra GG. Histopathology of Pulmonary Arterial Hypertension. In: Taichman
DB, Mandel J, editors: Pulmonary vascular disease, Philadelphia, 2006, Elsevrie Inc, pp 20-32.
21. D’alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension.
Results from a national prospective registry. Ann Intern Med 1991;115:343-349.
22. Moncada S, Gryglewski R, Bunting S, et al. An enzyme isolated from arteries transforms prostaglandin
endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976;263,663-665.
23. Humbert M, Sitbon O and Simmonneau G. Treatment of pulmonary arterial hypertension. N Eng J Med
2004;351:1425-1436.
24. McLaughlin VV, Shillington and Rich S. Survival in primary pulmonary hypertension: the impact of
epoprostenol therapy. Circ 2002;106:1477-1482.
25. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary
pulmonary hypertension. Eur Respir J 2005;25:244-249.
26. Survival in patients with idiopathic, familial and anorexigen associated pulmonary arterial
hypertension in the modern management era. Circulation 2010;122:156-163.
27. Badesch DB, Abman SH, Simmonneau G, et al. Medical therapy for pulmonary arterial hypertension:
updated ACCP evidence-based clinical practice guidelines. Chest 2007;131:1917-1928.
13
Chapter 1
General introduction